B cells: no longer bystanders in liver fibrosis.

Cytokines secreted by cells that mediate the innate and adaptive immune responses play a critical role in regulating the synthesis of ECM components by fibroblasts. Overexpression and deposition of ECM components are dominant features of fibrotic diseases, including hepatic fibrosis. The contribution of CD4+ Th2 cells to hepatic fibrosis has been well described. Now, in this issue of the JCI, Novobrantseva et al. provide data to suggest that hepatic B cells also play a role in liver injury (see the related article beginning on page 3072). In a carbon tetrachloride-induced mouse model of hepatic fibrosis, T cell-deficient mice developed severe liver fibrosis; however, in B cell-deficient animals, hepatic fibrosis was attenuated. This study provides new insight into our understanding of the cells involved in mediating the adaptive immune response that leads to hepatic fibrosis.

Regulatory effect of extracellular signal-regulated kinases (ERK) on type I collagen synthesis in human dermal fibroblasts stimulated by IL-4 and IL-13.

Synthesis of collagen is up-regulated by pro-fibrogenic growth factors and cytokines such as TGF-beta 1, IL-4, and IL-13 binding to their corresponding cell membrane receptors of fibroblasts. The ERK pathway is an important MAPK signaling pathway that is involved in regulating cell function. The aim of our studies was to examine effects of IL-4 and IL-13 on the ERK signaling pathway and its function in regulating type I collagen gene expression in human fibroblasts. We found that human dermal fibroblasts treated with IL-4 and IL-13 exhibited an increase in the activated ERK1/2 pathway. As well, pro-fibrogenic cytokines increased the promoter activity of type I collagen, and this activity decreased with cells that were co-transfected with dominant negative plasmids of ERK1 and 2. RT-PCR confirmed that collagen transcript levels decreased when cells were transfected with dn ERK1 and 2 and then further stimulated with IL-4 and IL-13. These results were also mirrored with collagen secretion assays. In addition, we studied the role for transcription factor Elk-1 known to be activated via the ERK pathway. Dominant negative Elk-1 showed inhibition of collagen promoter activity in fibroblasts transfected with full collagen type I promoter or two fragments which contain the Elk-1 binding site. Our results suggest that the modulation of collagen gene expression may occur via the ERK pathway and is mediated by Elk-1.

Molecular aspects of regulation of collagen gene expression in fibrosis.

Fibrosis, the hyper-accumulation of scar tissue, is characterized by the overproduction and deposition of type I and III collagen by fibroblasts and is the one of the main pathologic outcomes of the autoimmune disorder scleroderma. While the causes of fibrosis in scleroderma are unknown, cytokines such as TGF-beta, IL-4 and IL-13, play a crucial role in the stimulation of collagen production have been implicated in the disease process. In fibroblasts stimulation of collagen production by these cytokines is dependent on the Smad and STAT6 signaling pathways induced by TGF-beta and IL-4, IL-13 respectively. Furthermore, mounting evidence suggest cytokine crosstalk is relevant in the sclerotic process. Our laboratory demonstrated an increase in TGF-beta1 gene transcription from fibroblasts stimulated with IL-4. In addition, TSK/+ mice lacking the IL-4alpha receptor show impaired transcription of the TGF-beta1 gene and did not display fibrosis. Likewise, it appears that STAT6 plays a role in fibroblast TGF-beta1 transcription after IL-4 or IL-13 stimulation. These findings suggest that an epistatic interaction between IL-4 and TGF-beta may exist which is crucial for pathologic sclerotic activity.